Emphysema is a major cause of death and disability afflicting approximately 2 million people, costing more than $2.5 billion in yearly health care expenses and causing or contributing to 100,000 deaths per year in the United States alone. The disease is characterized by destruction of the alveolar wall, permanent enlargement of the airspaces and loss of lung recoil capability. Currently approved treatment regimens merely treat the symptoms and do not reverse the disease. New effective treatments are urgently needed. Recent studies suggest that hepatocyte growth factor (HGF), a pleiotropic cytokine, has multiple activities including promoting elastin synthesis, anti-apoptosis, suppressing inflammation, inducing angiogenesis and proliferation of lung epithelial and endothelial cells, and ultimately, lung regeneration. HGF production in pulmonary fibroblasts of emphysema patients is impaired. Using gene transfer, HGF has been shown to ameliorate emphysema in animal models. Thus HGF holds a great potential for the treatment of emphysema. To overcome drawbacks of protein- or gene-based HGF deliver in vivo, we have recently developed a small molecule mimetic of HGF, BB3, that recapitulates the full-range of bioactivities of HGF tested in vitro and in vivo. Moreover, in our pilot study, BB3 ameliorated emphysema in an animal model in a co-treatment design. Our long-range objective is to develop a small molecule mimetic of HGF as a drug for the treatment of emphysema. To pursue this endeavor, we plan to complete the following three specific aims in this SBIR Phase I application: Specific Aim-1: To test the in vivo efficacy of BB3 via i.p. administration in porcine pancreatic elastase(PPE)- induced rat model of emphysema, after emphysema is established (delayed treatment); Specific Aim-2: To investigate important molecular markers related to protection and regeneration of the lung by BB3 in PPE-induced emphysema in the rat (samples from Specific Aim-1) and cigarette smoking-induced emphysema in the mouse (samples from Specific Aim-3); Specific Aim-3: To test the in vivo efficiency of BB3 in the cigarette smoking-induced emphysema mouse model via delayed treatment. By completing the three specific aims described above, we will collect important information about the efficacy of BB3 in two experimental emphysema models under pre-existing disease condition, as well as molecular markers related to the treatment of BB3. These data will provide basis for further development of BB3 as a therapeutic for emphysema. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Pulmonary emphysema afflicts approximately 2 million people and costs 2.5 billion of health care expenses each year in US. Currently approved treatment regimens merely treat the symptoms and do not reverse the disease. New effective treatments are urgently needed. The objective of this SBIR Phase I application is to evaluate the efficacy of BB3 -- a small molecule mimetic of HGF in two well-established animal models of emphysema, and to provide a solid base for further therapeutic development of BB3 as a small molecule compound drug for emphysema. [unreadable] [unreadable] [unreadable]